EP1120100B1 - Antibakterielle mittel und ein herstellungsverfahren dafür - Google Patents

Antibakterielle mittel und ein herstellungsverfahren dafür Download PDF

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EP1120100B1
EP1120100B1 EP99970024A EP99970024A EP1120100B1 EP 1120100 B1 EP1120100 B1 EP 1120100B1 EP 99970024 A EP99970024 A EP 99970024A EP 99970024 A EP99970024 A EP 99970024A EP 1120100 B1 EP1120100 B1 EP 1120100B1
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Prior art keywords
oligosaccharide
antibacterial
sulfated polysaccharide
prepared
antibacterial agent
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French (fr)
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EP1120100A4 (de
EP1120100A1 (de
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Hideyuki Kabushiki Kaisha Yakult Honsha SHIBATA
Masato Kabushiki Kaisha Yakult Honsha NAGAOKA
Itsuko Kabushiki Kaisha Yakult Honsha TAKAGI
Shusuke Kabushiki Kaisha Yakult Honsha Hashimoto
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Yakult Honsha Co Ltd
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Yakult Honsha Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/731—Carrageenans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/737—Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to an antibacterial agent. More specifically, the invention relates to sulfated polysaccharides and oligosaccharide derivatives prepared by partially decomposing sulfated polysaccharides, which are effective for the eradication of Helicobactor pylori as the etiological microorganism of gastric ulcer or gastric cancer and typically include fucoidan, and a method for preparing the same.
  • oligosaccharide derivatives prepared from partially decomposed products of Nemacystus decipiens and green laver exert not only an action to promote the therapy of gastric ulcer but also exert an inhibitory action against the fixation of Helicobactor pylori and an antibacterial action against the microorganism (JP-A-11-60590).
  • the antibacterial action of the derivative substances is not yet satisfactory although the derivative substances have a strong action to promote the therapy of ulcer.
  • Some antibacterial agents comprising an anti-microbial metallic salt of polysaccharides (JP-A-8333213) or an antibacterial agent covalently bonded to chondroitin or chondroitin sulfate (US-A-4 489 065) have also already been described in the art.
  • the inventors have made investigations. Consequently, the inventors have prepared saccharide derivatives by modifying sulfated polysaccharides into oligosaccharide with acid treatment and additionally subjecting the resulting oligosaccharide to periodate oxidation, reaction with corresponding amines (antibacterial substance) and reductive treatment. Then, the inventors have verified that sulfated polysaccharides and the resulting saccharide derivatives have high affinity for Helicobactor pylori to show an excellent antibacterial effect. Hence, the invention has been achieved.
  • the antibacterial agent of the present invention is of a chemical structure containing a sulfated polysaccharide or an oligosaccharide prepared by partial decomposition of said sulfated polysaccharide and an antibacterial substance chemically bonded to said sulfated polysaccharide or said oligosaccharide, characterized in that said antibacterial substance is chemically bonded to the reduced end suggar of said sulplated polysaccharide or of said oligosaccharide.
  • the sulfated polysaccharide or oligosaccharide prepared by partial decomposition of said sulfated polysaccharide is selected from the group consisting of fucoidan, oligofucose prepared by partial decomposition of fucoidan, carrageenan and carrabiose prepared by partial decomposition of carrageenan.
  • the present invention also provides an antibacterial agent for use in the eradication of Helicobactor pylori, said agent comprising the aforementioned antibacterial agent as an effective component together with a pharmaceutically acceptable carrier or excipient in liquid or solid.
  • the present invention additionally provides a prophylactic and therapeutic agent of gastric ulcer, comprising the aforementioned antibacterial agent as an effective component together with a pharmaceutically acceptable carrier or excipient in liquid or solid.
  • a method for producing the antibacterial agent containing a sulfated polysaccharide or an oligosaccharide prepared by partial decomposition of the sulfated polysaccharide and an antibacterial substance chemically bonded to the sulfated polysaccharide or the oligosaccharide comprising the steps of:
  • an antibacterial substance is bonded to a sulfated polysaccharide or an oligosaccharide prepared by partial decomposition of the sulfated polysaccharide, such as fucoidan, carrageenan, rhamnan sulfate, chondroitin sulfate, heparin, dermatan sulfate and keratan sulfate. Therefore, the antibacterial agent has high affinity for Helicobactor pylori and exerts an antibacterial effect specific to Helicobactor pylori .
  • the sulfated polysaccharide or oligosaccharide prepared by partial decomposition thereof has high affinity for Helicobactor pylori , so that the sulfated polysaccharide or oligosaccharide is adsorbed or bonded to Helicobactor pylori to inhibit the fixation of Helicobactor pylori on gastric wall.
  • the present invention provides an antibacterial agent prepared by binding an antibacterial substance to a sulfated polysaccharide or oligosaccharide, namely a novel antibacterial agent capable of effectively allowing the antibacterial substance to exert the action against Helicobactor pylori .
  • fucoidan or carrageenan particularly, fucoidan might be preferable as the sulfated polysaccharide used in the present invention because of resultant high antibacterial effect.
  • the antibacterial agent according to the present invention has an antibacterial effect on pathological bacteria other than Helicobactor pylori , the antibacterial agent may also be applicable to these pathological bacteria.
  • the antibacterial agent has a chemical structure comprising a sulfated polysaccharide or an oligosaccharide prepared by partial decomposition of the sulfated polysaccharide and an antibacterial substance chemically bonded to the reduced end of the sulfated polysaccharide or the oligosaccharide, said chemical structure being represented by either one of the following formulae: Y-OCH(AH 2 NHR) n or Y-BH 2 NHR wherein, Y represents a sulfated polysaccharide or an oligosaccharide prepared by partial decomposition of the sulfated polysaccharide; A represents a carbon derived from aldehyde group occurring through the reduction of the reduced end sugar of Y and subsequent oxidation of the resulting product with an oxidant; B represents a carbon derived from the aldehyde group at the reduced end sugar of Y; R represents an antibacterial substance with a primary amino group or
  • Y in the formula is a sulfated polysaccharide or an oligosaccharide prepared by the partial decomposition thereof, such as fucoidan, carrageenan, rhamnan sulfate, chondroitin sulfate, heparin, dermatan sulfate and keratan sulfate, wherein some of the hydroxyl groups may be modified into sulfated esters.
  • the sulfated polysaccharide use can be made of oligosaccharide adjusted to a molecular weight of about 300 to 5,000, preferably, 300 to 1,000, through a combination of ultrafiltration membranes with different fractionation sizes.
  • fucoidan of a molecular weight of about 300 to 5,000, particularly 500 to 3,000 and carrageenan of a molecular weight of about 300 to 2,000, particularly 300 to 900.
  • R in the formula is an antibacterial substance with a primary amine or with an amino group introduced therein, such as cefem series, penicillin series, aminoglycoside series, macrolide series, pyridocarboxylate series, oxafem series, monobactam series, carbapenem series, tetracycline series, peptide series, chloramphenicol and sulfa agents, or derivatives thereof with spacers introduced therein.
  • cefem antibacterial agents include cefotaxime, cephalotin, cephaloridine, cephalexin, cefradine, cefazolin, ceftezol, cephapirin, cephacetrile, cefoxitin, cefmetazole, cefroxime, cefotiam, cephamandole, cefsulodine, ceftizoxime, ceftazidime, cefotetan, cefmenoxime, ceftriaxone, cefoperazone, cefbuperazone and cefixime.
  • Penicillin antibacterial agents include ampicillin, benzyl-PC, phenethicillin, propicilin, methicillin, zxacillin, cloxacillin, amoxicillin, cyclacillin, carbenicillin, sulbenicillin and piperacillin.
  • Aminoglycoside antibacterial agents include kanamycin, bekanamycin, tobramysin, dibekacin, gentamicin, amikacin, donkacin, neomycin B and paromomycin.
  • Macrolide antibacterial agents include erythromycin, kitasamycin, acetylkitasamycin, oleandomycin, josamycin, acetylspiramycin and midecamycin.
  • Pyridocarboxylate antibacterial agents include nalidixic acid, oxolinic acid, norfloxacin, piromidic acid, ofloxacin and ciprofloxacin.
  • Oxafem antibacterial agents include latamoxef.
  • Monobactam antibacterial agents include sulfanovan and monobactam.
  • Carbapenem antibacterial agents include thienamycin.
  • Tetracycline antibacterial agents include tetracycline, chlortetracycline, oxytetracycline, demethl chlortetracycline, doxycycline, methacycline, and minocycline.
  • Peptide antibacterial agents other than those included in any of the individual antibacterial agents described above, include gramicidin, penicillin, polymyxin, gramicidin S, viomycin and actinomycin.
  • each of the antibacterial agents has so high affinity for Helicobactor pylori, in particular, that each of the antibacterial agents is adsorbed or bonded specifically to Helicobactor pylori.
  • each of the antibacterial agents is particularly effective as an antibacterial agent for use against Helicobactor pylori .
  • the antibacterial agent specifically inhibits Helicobactor pylori so the agent can be used as a prophylactic and therapeutic agent of gastric ulcer.
  • Step 1 Extracting polysaccharides from sea algae (Phaeophyceae such as Nemacystus, Kurome and Fucus) containing fucoidan by known extraction processes (Cf. K. Matsuda., Biochemistry Experimental Methods, No. 20, “Separation and Purification of Polysaccharides", Gakkai Shuppan Center).
  • sea algae Phaeophyceae such as Nemacystus, Kurome and Fucus
  • Step 2 Dissolving the resulting fucoidan in a hydrochloric acid solution or trifluoroacetic acid solution of about 0.05 M to 0.1 M, heating the resulting solution at 100 °C for 10 to 20 minutes to modify the fucoidan into oligosaccharide, and neutralizing the solution with sodium hydroxide.
  • the oligosaccharide modification may satisfactorily be carried out by using fucoidanase (fucoidan decomposition enzyme). The reaction conditions then may appropriately be determined.
  • the NaBH4 is added to the oligosaccharide solution thus recovered, for reduction process at ambient temperature or 4 °C for 16 hours (Cf. JP-A-6-247861 and JP-A-7-138166).
  • Step 3 Desalting the solution of the oligosaccharide in the form of alditol as recovered by the procedures at the step 2, by electrodialysis (Microacylizer; manufactured by Asahi Chemical Industry, Co., Ltd.).
  • Step 4 Adding sodium metaperiodate to the solution at the step 3 for reaction at the temperature of ice for about one hour (the reaction time may satisfactorily be longer, depending on the structure of the sugar chain, for example the structure of an oligosaccharide with 1 ⁇ 3 bond).
  • Ethylene glycol at a volume excessive to periodic acid is added to the reaction solution, for reaction for another hour.
  • the resulting solution is desalted in the same manner as in the step 3.
  • oligosaccharide with an aldehyde group at the reduced end thereof can be recovered.
  • Step 5 Acetic acid is added to the sample prepared at the step 4 to a concentration of 0.5 M, for reaction at ambient temperature for 20 hours (under conditions for no promotion of the oxidation of the sugar chains at the side of the non-reduced end, the procedure may be skipped).
  • the reaction solution is desalted while ethylene glycol and the decomposition products thereof are removed, to recover oligosaccharide.
  • the oligosaccharide fraction may be prepared into a desired molecular size, using active charcoal chromatography and gel filtration, other than the purification by these processes.
  • Step 6 The oligosaccharide fraction is dissolved in water, followed by addition of an antibacterial agent to be introduced therein, for reaction at ambient temperature for one hour, to prepare a Schiff base.
  • Step 7 Borane dimethylamine is added to the solution recovered at the step 6, for reaction at ambient temperature for 20 hours to reduce the Schiff base.
  • any reducing agents suitable for the purpose of the invention can appropriately be used (for example, borane trimethylamine, NaCNBH3, NaBH4, etc.).
  • Step 8 After completion of the reaction, excess reagents are removed through ultrafiltration or dialysis. After removal of the excess reagents, the resulting reduced solution is dried by freeze-drying or further purified by ion exchange chromatography. It was verified that the oligosaccharide derivative thus recovered had high antibacterial effect against Helicobactor pylori as the etiological bacterium of gastric ulcer.
  • Polysaccharide derivatives prepared from fucoidan per se without the steps 2 and 3 can exert the same effect.
  • the dose of the antibacterial agent of the present invention can appropriately be selected in the same manner as for general pharmaceutical drugs, preferably according to the prescription of doctor.
  • a derivative prepared from oligofucose of a molecular weight of 500 to 3,000 is administered at a dose of 100 mg/day to 500 mg/day per adult, particularly at 200 mg/day to 300 mg/day per adult.
  • high antibacterial effect can be realized, together with the suppression of the side effects.
  • the larger molecular weight of fucoidan necessitates the higher dose for a certain level of the antibacterial effect. Therefore, in case where fucoidan of another molecular weight value is used, the content of fucoidan may be appropriately adjusted in accordance with the molecular weight thereof.
  • the form of the antibacterial agent according to the present invention can be selected appropriately.
  • the antibacterial agent is blended with a pharmaceutically acceptable carrier in liquid or solid, to which solvents, dispersants, emulsifiers, buffers, stabilizers, excipients, binders, disintegrators and/or lubricants are added if necessary, to formulate the antibacterial agent into tablets, granules, powders or capsules for use.
  • the present invention advantageously provides an antibacterial agent with high affinity for Helicobactor pylori and an antibacterial effect specific to Helicobactor pylori.
  • Cladosiphon okamuranus Tolida was desalted in deionized water. After that, the resulting alga was suspended in deionized water at a ratio of 1 kg of the alga per one liter of deionized water. With hydrochloric acid, the suspension was adjusted to pH 2. After heating the resulting solution at 100 °C for 10 minutes for extraction and filtering the alga through gauze, the resulting filtrate was further centrifuged to remove insoluble matters (9,000 rpm, 60 minutes).
  • Fucoidan was dissolved in distilled water to a concentration of 200 mg/mL, to which was added hydrochloric acid (or trifluoroacetic acid may be satisfactory) to a final concentration of 0.075 M to 0.1 M. After heating at 100 °C for 10 minutes, the resulting solution was cooled to ambient temperature. The solution was neutralized with NaOH, and then, NaBH 4 was added at a ratio of 200 mg per 1 g of fucoidan. The mixture reacted together at 4 °C for 20 hours.
  • hydrochloric acid or trifluoroacetic acid may be satisfactory
  • the reaction solution was adjusted to pH6 with acetic acid, which was then desalted with an electrodialyzer (Asahi Chemical Industry, Co., Ltd.; Microacylizer; AC220 membrane was used). After desalting, NalO 4 was added to the sample solution to a final concentration of 0.2 M, for reaction at the temperature of ice for one hour. Ethylene glycol of 2 equivalents corresponding to that of periodic acid was added to the reaction solution, for further reaction at the temperature of ice for one hour. The reaction solution was filtered through an ultrafiltration membrane of a fractionation molecular weight of 1,000 (manufactured by Millipore Co.), for concentration. The inner solution was freeze-dried, to recover an aldehyde derivative of oligofucose (yield of about 25 %).
  • the aldehyde derivative (5 g) of the oligosaccharide as produced in (1.2) was dissolved in water (100 mL), followed by addition of cefotaxime (CTX) of 1 g. Adding 1 mL of 0.5 M NaHCO 3 solution, reaction progressed at ambient temperature for one hour. After the reaction, 1 g of borane dimethylamine complex was added, for reaction at ambient temperature for 20 hours. The reaction solution was dialyzed throughout the day against a dialysis membrane of a fractionation molecular weight of 1,000. The resulting solution was freeze-dried, to recover the objective sample OF-CTX (yield of 1.14 g).
  • Fig. 1 shows 13 C-NMR chart of the resulting OF-CTX.
  • the structure of the OF-CTX is specifically shown by the following chemical formula (1).
  • Oligofucose (2 g) was dissolved in 80 mL of aqueous 40 % ethanol (0.05 M, NaCO 3 ). 350 mg of 12-aminolauric acid (C12) was added to the resulting solution, for reaction at 45 °C for one hour. 300 mg of borane dimethylamine was added, for reaction at 45 °C for 16 hours.
  • the solution was dialyzed against a dialysis tube of a fractionation molecular weight of 1,000 cut.
  • the freeze-dried dialysis product (875 mg) was dissolved in 10 mL of water, followed by addition of 500 mg of EDC. After reaction at ambient temperature for 2 hours, 350 mg of cefotaxime Na was added, for reaction for 4 hours. Then, the solution was dialyzed against a dialysis membrane of a fractionation molecular weight of 1,000 for 2 days. The resulting solution was freeze-dried to recover a derivative OF-C12-CTX at a yield of 384 mg.
  • the structure of the resulting OF-C12-CTX is specifically shown by the chemical formula (3) given below.
  • the resulting derivative was suspended in 40 mL of water, followed by addition of methanol until the derivative was dissolved therein.
  • the resulting solution was adjusted to pH 5 with hydrochloric acid, followed by addition of 3.5 g of water-soluble carbodiimide and 1.5 g of N-hydroxysuccinimide, for reaction at ambient temperature for 20 hours.
  • the reaction solution was dialyzed and freeze-dried.
  • the resulting dry product of 1.2 g was dissolved in water (20 mL).
  • Kappa carrageenan (10 g) was impregnated with water in 100 mL of 0.3N sulfuric acid. After permeation at 40 °C for 20 hours, heating was effected at 100 °C for 10 minutes. The resulting mixture was left to stand to ambient temperature, and was then neutralized. After removal of insoluble matters by centrifugation (20,000 rpm for 30 minutes), the resulting solution was desalted with Microacylizer and was then freeze-dried, to recover 9.74 g of carrabiose.
  • CarrabioAM carrabiose ampicillin derivative
  • CarrabioCTX carrabiose cefotaxime derivative
  • the activity inhibiting the growth of Helicobactor pylori was assayed by the following process.
  • To 1 mL of the Brucella culture medium was added 100 ⁇ L of a clinical isolate Helicobactor pylori strain (1.5 ⁇ 10 8 CFU/mL ), followed by addition of 0, 3, 6, 9 and 12 ⁇ L of 1 mg/mL OF-CTX or cefotaxime sodium CTX.
  • the turbidity was assayed (at A600 nm), to count the growth ratio. The results are shown in Fig. 2.
  • OF-CTX at a concentration of 6 ⁇ g/mL almost thoroughly inhibited the growth of Helicobactor pylori.
  • the activity was slightly lower than the activity of cefotaxime, but the cefotaxime content in the OF-CTX molecule was about 1/10 fold in molar ratio.
  • the OF-CTX activity is higher than the activity of CTX alone.
  • Helicobactor pylori is suspended in 25 mL of the Brucella culture medium. Then, each 500- ⁇ L portion is divided, to which is added 30 ⁇ L of the culture medium alone or 30 ⁇ L of the culture medium together with 1 mg/mL OF-CTX, for treatment at 0 °C for 0 to 25 minutes. After centrifugation at 14,000 rpm for 7 minutes, the precipitate is again suspended in 1 mL of the culture medium. The resulting suspension is divided in 100- ⁇ L portions. To the suspension is added 1 mL of the culture medium, for culturing at 37 °C for 3 days, to assay the turbidity at 600 nm. Consequently, the turbidity of the group preliminarily treated with OF-CTX is 0.153, while the turbidity of the control group is 0.494, which indicates that OF-CTX exerts a growth inhibitory effect at about 70 %.
  • the derivatives of fucoidan and oligofucose have antibacterial actions against Helicobactor pylori .
  • these derivatives retain the effect after rinsing.
  • these derivatives adhere to Helicobactor pylori and thus exert the effect.
  • these derivatives can be used as drugs advantageous for the therapeutic treatment of gastric ulcer and gastric cancer and as antibacterial agents with direction (specificity) to Helicobactor pylori.
  • the culture of Helicobactor pylori was suspended in a Brucella culture medium containing 5 % FCS to 1.5 x 10 8 CFU/mL. Each 200- ⁇ L portion was then inoculated in a 96-well microplate. Subsequently, each 2- ⁇ L portion of the carrabiose ampicillin derivative CarrabioAM or carrabiose cefotaxime derivative CarrabioCTX recovered in Example 2 (each at 1 mg/mL) was inoculated thereon. After agitation, the bacterium was cultured under slightly aerobic conditions at 37 °C for 3 days, to assay the turbidity at 600 nm.

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Claims (6)

  1. Antibakterielles Mittel mit einer chemischen Struktur, die ein sulfatiertes Polysaccharid oder ein Oligosaccharid, das durch partielle Zersetzung des sulfatierten Polysaccharids hergestellt wird, und eine antibakterielle Substanz umfasst, die chemisch an das sulfatierte Polysaccharid oder das Oligosaccharid gebunden ist, dadurch gekennzeichnet, dass die antibakterielle Substanz chemisch an den reduzierten Endzucker des sulfatierten Polysaccharids oder des Oligosaccharids gebunden ist.
  2. Antibakterielles Mittel nach Anspruch 1, in dem die chemische Struktur durch eine der folgenden Formeln dargestellt wird: Y-OCH(AH2NHR)n oder Y-BH2NHR worin Y ein sulfatiertes Polysaccharid oder ein Oligosaccharid darstellt, das durch partielle Zersetzung des sulfatierten Polysaccharids hergestellt wird; A einen Kohlenstoff darstellt, der von einer Aldehydgruppe abstammt, die durch die Reduktion des reduzierten Endzuckers von Y und anschließende Oxidation des resultierenden Produkts mit einem Oxidationsmittel auftritt; B einen Kohlenstoff darstellt, der von der Aldehydgruppe am reduzierten Endzucker von Y abstammt; R eine antibakterielle Substanz mit einer primären Aminogruppe oder einer darin eingeführten Aminogruppe darstellt oder ein Derivat einer antibakteriellen Substanz darstellt, das durch Binden einer antibakteriellen Substanz durch einen Abstandshalter an den Kohlenstoff A oder den Kohlenstoff B hergestellt wird; und n = 1 oder 2.
  3. Antibakterielles Mittel nach Anspruch 1, in dem das sulfatierte Polysaccharid oder das Oligosaccharid, das durch partielle Zersetzung des sulfatierten Polysaccharids hergestellt wird, ausgewählt ist aus der Gruppe bestehend aus Fucoidan, Oligofucose, die durch partielle Zersetzung von Fucoidan hergestellt wird, Carrageenan und Carrabiose, die durch partielle Zersetzung von Carrageenan hergestellt wird.
  4. Antibakterielles Mittel zur Verwendung gegen Helicobactor pylori, umfassend ein antibakterielles Mittel nach Anspruch 1 als wirksame Komponente zusammen mit einem pharmazeutisch annehmbaren Träger oder Hilfsstoff.
  5. Prophylaktisches und therapeutisches Mittel für Magenulkus, umfassend ein antibakterielles Mittel nach Anspruch 1 als wirksame Komponente zusammen mit einem pharmazeutisch annehmbaren Träger oder Hilfsstoff.
  6. Verfahren zur Herstellung eines antibakteriellen Mittels nach Anspruch 1, umfassend die Schritte:
    Öffnen des Rings der Aldehydgruppe des Zuckerrests, der am reduzierten Ende des sulfatierten Polysaccharids oder des Oligosaccharids, das durch partielle Zersetzung des sulfatierten Polysaccharids hergestellt wird, verbleibt, direkt oder durch oxidative Zersetzung, um eine Oligosaccharid-Fraktion zu gewinnen;
    Ermöglichen, dass die Amingruppe einer antibakteriellen Substanz, welche der Ring-geöffneten Aldehydgruppe entspricht, mit der Oligosaccharid-Fraktion reagiert, um eine Schiff-Base herzustellen; und
    Reduzieren der resultierenden Schiff-Base.
EP99970024A 1998-10-05 1999-10-04 Antibakterielle mittel und ein herstellungsverfahren dafür Expired - Lifetime EP1120100B1 (de)

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JP28214398 1998-10-05
JP28214398 1998-10-05
PCT/JP1999/005448 WO2000020009A1 (en) 1998-10-05 1999-10-04 Antibacterial agents and process for producing the same

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EP1120100A1 EP1120100A1 (de) 2001-08-01
EP1120100A4 EP1120100A4 (de) 2003-06-11
EP1120100B1 true EP1120100B1 (de) 2005-08-17

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US (1) US7498317B2 (de)
EP (1) EP1120100B1 (de)
JP (1) JP4439119B2 (de)
KR (1) KR100698232B1 (de)
AU (2) AU6001999A (de)
CA (1) CA2346132C (de)
DE (1) DE69926770T2 (de)
WO (1) WO2000020009A1 (de)

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FI20011403A7 (fi) 2001-06-29 2002-12-30 Carbion Oy Menetelmä ja koostumukset vatsan sairauksien hoitoon
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US20110245198A1 (en) * 2009-03-23 2011-10-06 Nikolay Nifantiev Enhanced treatments to kill or debilitate pathogenic microorganisms of a mammalian body
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KR20010075470A (ko) 2001-08-09
AU6001999A (en) 2000-04-26
EP1120100A4 (de) 2003-06-11
EP1120100A1 (de) 2001-08-01
US20050130934A1 (en) 2005-06-16
CA2346132A1 (en) 2000-04-13
DE69926770D1 (de) 2005-09-22
WO2000020009A1 (en) 2000-04-13
CA2346132C (en) 2008-02-12
DE69926770T2 (de) 2006-06-29
KR100698232B1 (ko) 2007-03-21
AU2003244540A1 (en) 2003-09-25
US7498317B2 (en) 2009-03-03

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